US3641027A - 5 6 78-tetrahydro - 5 - oxo-pyrid o(23-d)-pyrimidine - 6 -carbonitriles and related compounds - Google Patents

5 6 78-tetrahydro - 5 - oxo-pyrid o(23-d)-pyrimidine - 6 -carbonitriles and related compounds Download PDF

Info

Publication number
US3641027A
US3641027A US752485A US3641027DA US3641027A US 3641027 A US3641027 A US 3641027A US 752485 A US752485 A US 752485A US 3641027D A US3641027D A US 3641027DA US 3641027 A US3641027 A US 3641027A
Authority
US
United States
Prior art keywords
pyrimidine
tetrahydro
cyanoethyl
oxo
following
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US752485A
Inventor
Arthur A Santilli
Dong H Kim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
American Home Products Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Home Products Corp filed Critical American Home Products Corp
Application granted granted Critical
Publication of US3641027A publication Critical patent/US3641027A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • R is selected from the class consisting of chlorobenzyl, ethyl morpholino, propyl morpholino, lower alkyl, phen (lower) alkyl, lower alkoxy (lower) alkyl, di (lower) alkylamino lower alkyl; and
  • Ice R is lower alkyl, phenyl, halophenyl, lower alkylphenyl, and lower alkoxyphenyl.
  • lower alkyl, lower alkoxy, and the like describe groups containing from about 1 to about 4 carbon atoms.
  • R and R are as defined above, and R is methoxy or ethoxy.
  • Typical examples of the compounds of this invention which are depicted by structural Formula I are 5, 6,7,8- tetrahydro 5 oxo 8 phenthyl 2 phenylpyrido [2,3- d]pyrimidine-6-carbonitrile and 8-(p-chlorobenzyl)-5,6, 7,8-tetrhydro 5 oxo 2 phenylpyrido[2,3-d]pyrididine-6-carbonitrile.
  • Typical examples of the compounds of this invention which are depicted by structural Formula II are 4-[(2- cyanoethyl)-(phenyl)amino] 2 phe'nyl 5 pyrimidinecarboxylic acid, ethyl ester and 4-[(2-cyanoethyl) (2-morpholinoethyl)amino]-2-phenyl 5 pyrimidinecarboxylic acid, ethyl ester.
  • the new and novel compounds of this invention may be prepared by the process which is hereinafter schematically illustrated:
  • the 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6- carbonitriles (I) of this invention may be prepared by a two step process.
  • a mixture of S-carbalkoxy-4-chloropyrimidine (III) and 3-alkylaminopropionitrile (IV) in a reaction inert organic solvent, such as an alkanol or dirnethylformamide is heated with stirring at a temperature range from about 60 to about degrees C. for a period of about 1 to 4 hours, affording the intermediate product 4 [(2 cyanoethyl)-alkylamino]-5- pyrimidine carboxylic acid esters (11).
  • the reaction is carried out in ethanol, if R is ethoxy, or in methanol if R is methoxy, at the reflux temperature for about two hours, but time is not critical.
  • an acid scavenger such as sodium carbonate, is utilized to neutralize hydrochloric acid generated in the reaction.
  • the intermediates may be separated and Purified by means well known in the art.
  • the product may be separated by standard recovery means, for example, removal of organic solvent by evaporation and treatment of the residue with water to remove any inorganic salt.
  • the product may be purified by recrystallization from an organic solvent such as benzene-petroleum ether, cyclohexane, pentane and the like.
  • the new and novel intermediate product (II) is added to a solution of metallic sodium in an alkanol, methanol being used where R is methoxy and ethanol being used where R is ethoxy. While other metals may be used, as is known in the art, sodium and potassium are preferred because they will dissolve in the solvents used in the reaction and because they produce strong bases.
  • the reaction mixture is heated at a temperature range of about 60 to 80 degrees C., preferably the reflux temperature, for a period of about /2 to 3 hours, preferably from about 1 to 2% hours.
  • the product may be recovered by well known means, for instance, the reaction mixture may be evaporated to dryness, the residue dissolved in water and the solution acidified to precipitate the product.
  • the precipitate thus afforded may be recrystallized from a suitable solvent for instance from acetone and water, ethanol, Z-ethoxyethanol-water, or the like, affording the pure product, 5,6,7 ,8 tetrahydro oxopyrido [2,3-d] pyrimidine-6-carbonitrile (I).
  • 3-(substituted amino)propionitrile starting materials used in the practice of the present invention have been described in the literature except 3-(2-methoxyethylamino) propionitrile.
  • the latter compound may be prepared by adding 159 grams of acrylonitrile, dropwise over a period of 90 minutes while maintaining the temperature below 30 C., to a solution of 33.6 grams of 2- methoxyethylamine in 200 milliliters of absolute ethanol. The reaction mixture is allowed to stand at room temperature for about four hours and then is heated to reflux for about one hour. The ethanol is removed by evaporation, and the residue is fractionally distilled, affording 33.8 grams of the desired starting material distilling at 94-96 C. at a pressure of 0.5 millimeter of mercury.
  • the new and novel 4-[-(2-cyanoethyl)alkylamino]-5- pyrimidine carboxylic acid esters (II) of this invention are useful as intermediates in the preparation of the new and novel 5,6,7,8-tetrahydro-5-oxopyridol[2,3-d]pyrimidine-6-carbonitriles (I) of this invention.
  • Both the intermediate compounds of Formula II and the products of Formula I are useful as central nervous system depressants. That is, they produce a calming effect in the host.
  • the in vivo effects are tested as follows.
  • the compound to be tested is administered orally or intraperitoneally to three mice (14 to 24 grams) at each of the following doses: 400, 127, 40 and 12.7 mg./kg.
  • the animals are watched for a minimum of two hours during which time signs of general stimulation, (i.e., increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching), general depression (i.e., decreased spontaneous motor activity, decreased respiration) autonomic activity, (i.e., miosis, mydriasis, diarrhea) are noted.
  • signs of general stimulation i.e., increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching
  • general depression i.e., decreased spontaneous motor activity, decreased respiration
  • autonomic activity i.e., miosis, mydriasis, diarrhea
  • the 5,6,7,8 tetrahydro-S-oxopyrido[2,3-d] pyrimidine- 6-carbonitriles (I) of this invention induce central nervous system depressant effects at 40 to 400 mg./kg. of host 4 body weight when administered orally or at 12.7 to 40 mgJkg. when administered intraperitoneally.
  • the compounds of this invention may be administered alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice.
  • they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk, sugar, certain types of clay and so forth. They may be administered sublingually in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups; and then dehydrated sufficiently to make it suitable for pressing into a solid form.
  • They may be administered orally in the form of solutions or they may be injected parenterally, that is, intra-muscularly, intravenously or subcutaneously.
  • parenteral administration may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.
  • the dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing harmful or deleterious side effects.
  • EXAMPLE IV This example shows the preparation of 4-[(2-cyanoethyl)(phenethyl)amino]-2-phenyl pyrimidinecarboxylic acid, ethyl ester, a compound of structure (II).
  • EXAMPLE VII The following example illustrates the preparation of 4-[(2-cyanoethyl) (2 morpholinoethyl)amino]-2-phenyl- S-pyrimidinecarboxylic acid, ethyl ester, a compound of structure (11).
  • EXAMPLE XII The following illustrates the preparation of 4-[2-cyanoethyl) (2 diethylaminoethyl) amino]-2-phenylpyrimidine- 5-carboxylic acid, ethyl ester, a compound of structure (II).
  • EXAMPLE XV The following illustrates the preparation of 4-[p-chlorobenzyl(2-cyanoethyl)amino] 2 phenylpyrimidine-S- carboxylic acid, ethyl ester.
  • EXAMPLE XXV The following illustrates the preparation of 5,6,7,8- tetrahydro 8 (2 morpholinoethyl)-5-oxo-2-phenylpyrido[2,3-d]pyrimidine 6 carbonitrile, a compound of structure (I).
  • R is selected from the group consisting of chlorobenzyl, lower alkyl, phenloweralkyl, lower alkoxy (lwer)alkyl and di(lower)alkylamino (lower)a1kyl;
  • R is selected from the group consisting of lower alkyl, phenyl, halophenyl, lower alkylphenyl, and lower alkoxyphenyl.
  • a compound as defined in claim 1 which is 5,6,7,8- tetr'ahydro 5 oxo-8-phenylethyl-2-pheny1pyrido[2,3-d] pyrimidine-6-carbonitrile.
  • a compound as defined in claim 1 which is 5,6,7,8- tetrahydro 8 (2 methoxyethyl)-5-oXo-2-pheny1pyrido [2,3-d]pyrimidine-6-carbonitrile.
  • a compound as defined in claim 1 which is 8-(pchlorobenzyl) 5,6,7,8 tetrahydro-S-oxo-2-phenylpyrido [2,3-d]pyrimidine-6-carbonitri1e.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

THE DISCLOSURE IS DIRECTED TO 5,6,7,-TETAHYDRO-5-OXOPYRIDO(2,3-D)PYRIMIDINE-6-CARBONITRILES AND TO 4-((2CYANOETHYL)ALKYLAMINO)-5-PRIMIDINE CARBOXYLIC ACID ESTERS WHICH ARE INTERMEDIATES IN THEIR PREPARATION. BOTH THE FINAL PRODUCTS AND THE INTERMEDIATES HAVE CENTRAL NERVOUS SYSTEM ACTIVITY AS DEPRESSANTS.

Description

United States Patent 3,641,027 5,6,7,8-TETRAHYDRO 5 0X0-PYRIDO[2,3-d]- PYRIMIDINE 6 CARBONITRILES AND RE- LATED COMPOUNDS Arthur A. Santilli, Havertown, and Doug H. Kim, Wayne,
Pa., assignors to American Home Products Corporation, New York, N.Y. No Drawing. Filed Aug. 14, 1968, Ser. No. 752,485 Int. Cl. C07d 57/20 US. Cl. 260256.4 F 5 Claims ABSTRACT OF THE DISCLOSURE The disclosure is directed to 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6-carb0nitriles and to 4-[ (2- cyanoethyl)alkylamino1-5-primidine carboxylic acid esters which are intermediates in their preparation. Both the final products and the intermediates have central nervous system activity as depressants.
are fully aromatic and contain no 5-oxo group. The compounds of the present invention are distinguished from the prior art inter alia by the presence of the 5-oxo group. Some of the compounds within the purview of the present invention are exemplified by those having the following formula:
m lq Where R is selected from the class consisting of chlorobenzyl, ethyl morpholino, propyl morpholino, lower alkyl, phen (lower) alkyl, lower alkoxy (lower) alkyl, di (lower) alkylamino lower alkyl; and
3,641,027 Patented Feb. 8, 1972 "Ice R is lower alkyl, phenyl, halophenyl, lower alkylphenyl, and lower alkoxyphenyl.
As used herein the terms lower alkyl, lower alkoxy, and the like describe groups containing from about 1 to about 4 carbon atoms.
Also within the purview of the present invention are compounds exemplified by the following formula which, as is explained below, are intermediates in the preparation of the compounds having structural Formula I:
where R and R are as defined above, and R is methoxy or ethoxy.
Typical examples of the compounds of this invention which are depicted by structural Formula I are 5, 6,7,8- tetrahydro 5 oxo 8 phenthyl 2 phenylpyrido [2,3- d]pyrimidine-6-carbonitrile and 8-(p-chlorobenzyl)-5,6, 7,8-tetrhydro 5 oxo 2 phenylpyrido[2,3-d]pyrididine-6-carbonitrile.
Typical examples of the compounds of this invention which are depicted by structural Formula II are 4-[(2- cyanoethyl)-(phenyl)amino] 2 phe'nyl 5 pyrimidinecarboxylic acid, ethyl ester and 4-[(2-cyanoethyl) (2-morpholinoethyl)amino]-2-phenyl 5 pyrimidinecarboxylic acid, ethyl ester.
The new and novel compounds of this invention may be prepared by the process which is hereinafter schematically illustrated:
dechloroamination k I v R2/ CH CH CN 0 cycllzation ReQQ where R R and R are defined as above.
As will be understood by those skilled in the art, the compounds having Formula I may exist as tautomers of the structures shown.
The 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6- carbonitriles (I) of this invention may be prepared by a two step process. In the first step a mixture of S-carbalkoxy-4-chloropyrimidine (III) and 3-alkylaminopropionitrile (IV) in a reaction inert organic solvent, such as an alkanol or dirnethylformamide, is heated with stirring at a temperature range from about 60 to about degrees C. for a period of about 1 to 4 hours, affording the intermediate product 4 [(2 cyanoethyl)-alkylamino]-5- pyrimidine carboxylic acid esters (11). Preferably the reaction is carried out in ethanol, if R is ethoxy, or in methanol if R is methoxy, at the reflux temperature for about two hours, but time is not critical. Preferably an acid scavenger, such as sodium carbonate, is utilized to neutralize hydrochloric acid generated in the reaction.
The intermediates may be separated and Purified by means well known in the art. For instance, when the reaction is complete, the product may be separated by standard recovery means, for example, removal of organic solvent by evaporation and treatment of the residue with water to remove any inorganic salt. The product may be purified by recrystallization from an organic solvent such as benzene-petroleum ether, cyclohexane, pentane and the like.
In the second step the new and novel intermediate product (II) is added to a solution of metallic sodium in an alkanol, methanol being used where R is methoxy and ethanol being used where R is ethoxy. While other metals may be used, as is known in the art, sodium and potassium are preferred because they will dissolve in the solvents used in the reaction and because they produce strong bases. The reaction mixture is heated at a temperature range of about 60 to 80 degrees C., preferably the reflux temperature, for a period of about /2 to 3 hours, preferably from about 1 to 2% hours.
When the reaction is complete, the product may be recovered by well known means, for instance, the reaction mixture may be evaporated to dryness, the residue dissolved in water and the solution acidified to precipitate the product. The precipitate thus afforded may be recrystallized from a suitable solvent for instance from acetone and water, ethanol, Z-ethoxyethanol-water, or the like, affording the pure product, 5,6,7 ,8 tetrahydro oxopyrido [2,3-d] pyrimidine-6-carbonitrile (I).
All of the 3-(substituted amino)propionitrile starting materials used in the practice of the present invention have been described in the literature except 3-(2-methoxyethylamino) propionitrile. The latter compound may be prepared by adding 159 grams of acrylonitrile, dropwise over a period of 90 minutes while maintaining the temperature below 30 C., to a solution of 33.6 grams of 2- methoxyethylamine in 200 milliliters of absolute ethanol. The reaction mixture is allowed to stand at room temperature for about four hours and then is heated to reflux for about one hour. The ethanol is removed by evaporation, and the residue is fractionally distilled, affording 33.8 grams of the desired starting material distilling at 94-96 C. at a pressure of 0.5 millimeter of mercury.
The new and novel 4-[-(2-cyanoethyl)alkylamino]-5- pyrimidine carboxylic acid esters (II) of this invention are useful as intermediates in the preparation of the new and novel 5,6,7,8-tetrahydro-5-oxopyridol[2,3-d]pyrimidine-6-carbonitriles (I) of this invention. Both the intermediate compounds of Formula II and the products of Formula I are useful as central nervous system depressants. That is, they produce a calming effect in the host.
In the pharmacological evaluation of the biological activity of the compounds of this invention, the in vivo effects are tested as follows. The compound to be tested is administered orally or intraperitoneally to three mice (14 to 24 grams) at each of the following doses: 400, 127, 40 and 12.7 mg./kg. The animals are watched for a minimum of two hours during which time signs of general stimulation, (i.e., increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching), general depression (i.e., decreased spontaneous motor activity, decreased respiration) autonomic activity, (i.e., miosis, mydriasis, diarrhea) are noted.
If a compound demonstrates no activity following oral administration, the procedure is repeated following intraperitoneal administration.
The 5,6,7,8 tetrahydro-S-oxopyrido[2,3-d] pyrimidine- 6-carbonitriles (I) of this invention induce central nervous system depressant effects at 40 to 400 mg./kg. of host 4 body weight when administered orally or at 12.7 to 40 mgJkg. when administered intraperitoneally.
When the compounds of this invention are employed as described above, they may be administered alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk, sugar, certain types of clay and so forth. They may be administered sublingually in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups; and then dehydrated sufficiently to make it suitable for pressing into a solid form. They may be administered orally in the form of solutions or they may be injected parenterally, that is, intra-muscularly, intravenously or subcutaneously. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.
The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing harmful or deleterious side effects.
In order more clearly to disclose the nature of the present invention, specific examples of the practice of the invention are hereinafter given. It should be understood, however, that this is done solely by way of example and is intended neither to delineate the scope of the invention nor limit the ambit of the appended claims.
EXAMPLE I This example shows the preparation of 4-[(2-cyanoethyl)-methylamino] 2 phenyl-S-pyrimidinecarboxylic acid, ethyl ester, a compound of structure (II).
A mixture of 2.6 grams (g.) of 5-carbethoxy-4-chloro- 2-phenylpyrimidine, 0.9 g. of 3-methylaminopropionitrile and 1.1 g. of sodium carbonate in 50 milliliters (ml.) of ethanol is heated with stirring under reflux for 2 hours. The reaction mixture is taken to dryness on a rotary evaporator. The residue is triturated with 50 ml. of water and filtered under suction. Recrystallization from benzene-petroleum ether afforded 1.5 g. of product having a melting point of 83-85 C.
Based on the formula C H N O it is calculated that the elemental analysis by weight would be 65.79 percent carbon, 5.85 percent hydrogen and 18.05 percent nitrogen. The product is analysed and the content is found to be 65.74 percent carbon, 5.77 percent hydrogen, and 17.84 percent nitrogen. The foregoing may be expressed:
Analysis.-Ca1culated for C H N O (percent): C, 65.79; H, 5.85; N, 18.05. Found (percent): C, 65.74; H, 5.77; N, 17.84.
EXAMPLES II-III Following the procedure of Example I, but substituting appropriate starting materials the following products may be prepared:
(II) 4-[ (Z-cyanoethyl)ethylamino]-2- (p-tolyl) 5- pyrimidinecarboxylic acid, methyl ester.
(III) 4- [butyl 2-cyanoethyl) amino] -2-methyl-5- pyrimidinecarboxylic acid, methyl ester.-
EXAMPLE IV This example shows the preparation of 4-[(2-cyanoethyl)(phenethyl)amino]-2-phenyl pyrimidinecarboxylic acid, ethyl ester, a compound of structure (II).
Following the procedure of Example I, 4-[(2-cyano- 5 Following the procedure of Example I, but substituting appropriate starting materials, the following products are afforded:
(V) 2- (p-butylphenyl -4- (4-phenbutyl) (Z-cyanoethyl)amino]-5-pyrimidinecarboxylic acid, methyl ester.
(VI) 2-butyl-4-[benzyl (Z-cyanoethyl amino] -5- pyrimidinecarboxylic acid, methyl ester.
EXAMPLE VII The following example illustrates the preparation of 4-[(2-cyanoethyl) (2 morpholinoethyl)amino]-2-phenyl- S-pyrimidinecarboxylic acid, ethyl ester, a compound of structure (11).
Following the procedure of Example I, 4-[(2-cyanoethyl)(2-morpholinoethyl)amino] 2 phenyl-S-pyrimidinecarboxylic acid, ethyl ester is prepared from 2.6 g. of 5-carbethoxy-4-chloro-2-phenylpyrimidine, 1.8 g. of 3- (2-morpholinoethylamino)propionitrile and 1.1 g. of sodium carbonate in 50 ml. of ethanol. The oily residue crystallizes on standing. Recrystallization from cyclohexane aifords 2.1 g. of product having a melting point of 8890 C.
Analysis.-Calculated for C22H27N5O3 (percent): C, 64.53; H, 6.65; N, 17.10. Found (percent): C, 64.64; H, 6.78; N, 16.96.
' EXAMPLE VIII Following the procedure of Example I, but substituting an appropriate starting material, the following product is afforded:
(VIII) 4- (2-cyanoethyl) (3-morpholinopropyl) amino] 2-(p-methoxyphenyl)-5-pyrimidinecarboxylic acid,
methyl ester.
EXAMPLE IX Following the procedure of Example I, but substituting appropriate starting materials, the following products are afforded:
(x 2-(m-butoxyphenyl)-4-[(2-cyanoethyl) (4-eth0Xybutyl) amino] -5-pyrimidinecarboxylic acid, ethyl ester.
6 (XI) 4-[ (butoxyethyl) (2-cyanoethyl) amino]-2- (o-ethoxyphenyl)-5-pyrimidinecarboxylic acid, methyl ester.
EXAMPLE XII The following illustrates the preparation of 4-[2-cyanoethyl) (2 diethylaminoethyl) amino]-2-phenylpyrimidine- 5-carboxylic acid, ethyl ester, a compound of structure (II).
Following the procedure of Example I, 4-[(2-cyanoethyl)(Z-diethylaminoethyl)amino] 2 phenylpyrimidine 5 carboxylic acid, ethyl ester is prepared from 2.6 g. of 5-carbethoxy-4-chloro-2-phenylpyrimidine, 1.6 g. of 3-(2-diethylaminoethylamino)propionitrile and 1.1 g. of sodium carbonate in 50 m1. of ethanol. The product is recrystallized from pentane giving a product having a melting point of 42-45 C.
Analysis.-Calculated for C H N O (percent): C, 66.81; H, 7.39; N, 17.71. Found (percent): C, 66.95; H, 7.48; N, 17.41.
EXAMPLES XIII-XIV Following the procedure of Example I, but substituting appropriate starting materials, the following products are afforded:
(XIII) 4-[ (Z-cyanoethyl) (4-dimethylaminobutyl) amino]-2-ethylpyridine-5-carboxylic acid, methyl ester.
(XIV) 4-[ (2-cyanoethyl) 3-dimethylaminopropyl amino) ]-2-(p-tolyl) pyrimidine-S-carboxylic acid, ethyl ester.
EXAMPLE XV The following illustrates the preparation of 4-[p-chlorobenzyl(2-cyanoethyl)amino] 2 phenylpyrimidine-S- carboxylic acid, ethyl ester.
Following the procedure of Example I, 4-[p-chlorobenzyl(2 cyanoethyl)amino] 2 phenylpyrimidine-S- carboxylic acid, ethyl ester is prepared from 2.6 g. of S-carbethoxy 4 chloro-2-phenylpyrimidine, 1.9 g. of 3-(p-chlorobenzylamino)propionitrile and 1.1 g. of sodium carbonate in 50 ml. of ethanol. The product when crystallized from cyclohexane-petroleum ether has a melting point of 9395 C.
Analysis.Calculated for C H ClN O (percent): C, 65.63; H, 5.03; CI, 8.42; N, 13.31. Found (percent): C, 65.32; H, 5.11; Cl, 8.55; N, 13.19.
EXAMPLES XVI-XVIII Following the procedure of Example I, but substituting appropriate starting materials, the following products are afforded:
(XVI) 4- [m-chlorobenzyl Z-cyanoethyl amino]-2- (mchlorophenyl)pyrimidine-S-carboxylic acid, methyl ester.
(XVII) 4- [o-chlorobenzy1( 2-cyanoethyl) amino] -2- (piodophenyl)pyrimidine-S-carboxylic acid, ethyl ester.
(XVIII) 4- [p-chlorobenzyl(2-cyanoethyl amino] 2- (ofiuorophenyl)pyrimidine-S-carboxylic acid, methyl ester.
EXAMPLE XIX This example illustrates the preparation of 5,6,7,8-tetrahydro-8-methyl 5 oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carbonitrile, a compound of structure (I).
To a solution of 0.1 g. of sodium in 50 ml. of ethanol there is added 1 g. of 4-[(2-cyanoethyl)methylamino]-2- phenyl 5 pyrimidinecarboxylic acid, ethyl ester. The reaction mixture is heated under reflux for 1 hour. The reaction mixture is cooled in ice and the precipitate which deposits is collected on a filter. This material is dissolved in 50 ml. of water, and the solution is made acidic with 20 percent acetic acid solution. A yellow material precipitates out of solution. Upon recrystallization from ethanol 0.3 g. of product is obtained having a melting point of 218-220 C.
7 AnaZysz's.-Calculated for C I-I N O (percent): C, 68.17; H, 4.58; N, 21.20. Found (percent): C, 68.41; H, 4.51; N, 21.30.
EXAMPLES XX-XXI Following the procedure of Example XIX but substituting appropriate starting materials, the following products are afforded:
(XX) 8-ethyl-5,6,7,8-tetrahydro-2-(p-tolyl)-5-oxo pyrido [2,3-d] pyrimidine-6-carbonitrile.
(XXI) 8-butyl-5,6,7,8-tetrahydro-2methyl-5-oxopyrido [2,3-d] pyrimidine-G-carbonitrile.
EXAMPLE XXII This example illustrates the preparation of 5,6,7,8-tetrahydro-S-oxo 8 phenethyl-Z-phenylpyrido[2,3-d]pyrimidine-6-carbonitrile, a compound of structure (I).
To a solution of 0.23 g. of sodium in 100 ml. of ethanol is added 4.1 g. of 4-[(2-cyanoethyl) (phenethyl) amino] 2 phenyl-S-pyrimidinecarboxylic acid, ethyl ester. The reaction mixture is heated under reflux for 2.5 hours, then evaporated to dryness in a rotary evapo rator. The residue is dissolved in 50 ml. of hot water and the solution is acidified with 3 normal (3 N) acetic acid to pH 6. The precipitate thus afforded is recrystallized from acetone-water giving 2.7 g. of product having a melting point of 199-202 C.
Analysis.--Calculated for C H N O (percent): C, 74.55; H, 5.12; N, 15.81. Found (percent): C, 74.57; H, 5.09; N, 15.51.
EXAMPLES XXIII-XXIV Following the procedure of Example XXII but substituting an appropriate starting material, the following products are afforded:
(XXIII) 2- (p-butylphenyl) -5,6,7,8-tetrahydro--oxo- 8- (4-phenbutyl) -pyrido [2,3-d1pyrimidine-6- carb onitrile.
(XXIV) 8-benzyl-2- (p-butylphenyl) -5,6,7,8-tetrahydro- S-oxo-pyrido [2,3-d] pyrimidine-6-carbonitrile.
EXAMPLE XXV The following illustrates the preparation of 5,6,7,8- tetrahydro 8 (2 morpholinoethyl)-5-oxo-2-phenylpyrido[2,3-d]pyrimidine 6 carbonitrile, a compound of structure (I).
Following the procedure of Example XXII, 5,6,7,8- tetrahydro 8 (2 morpholinoethyl)-5-oxo-2-phenylpyrido[2,3-d] pyrimidine 6 carbonitrile is prepared from 6.5 g. of 4-[(2-cyanoethyl) (2-morpholinoethyl)amino]- 2-phenyl 5 pyrimidinecarboxylic acid, ethyl ester in 50 ml. of ethanol containing 0.35 g. of sodium. After recrystallization from 2-ethoxyethanol-water, the product is obtained having a melting point of 107109 C.
Analysis.Calculated for C H N O (percent): C, 66.10; H, 5.82; N, 19.27. Found (percent): C, 66.17; H, 5.61; N, 19.08.
EXAMPLES XXVI-XXIX Following the procedure of Example XXII but substituting appropriate starting materials, the following products are afforded:
(XXVI) 5 ,6,7,8-tetrahydro-2- (p-methoxyphenyl) -8- (3-morpholinopropyl) -5-oxopyrido [2,3-d] pyrimidine-6-c arbonitrile.
(XXVII) 8 (Z-diethylaminoethyl -5,6,7,8-tetrahydro-5- oxo-Z-phenylpyrido [2,3-d] pyrimidine-G-carbonitrile.
(XXV III) Z-ethyl-5,6,7,8-tetrahydro-8- (4-dimethyl-aminobutyl)-5-oxopyrido [2,3-d] pyrimidine-6- carbonitrile.
(XXIX) 5,6,7,8-tetrahydro-8- 3 -dimethylaminopropyl) 2- (p-tolyl)-5-oxopyrido [2,3-d] pyrimidine-6- carbonitrile.
8 EXAMPLE xxx The following illustrates the preparation of 5,6,7,8- tetrahydro-S-(Z-methoxyethyl)-5-oxo 2 phenylpyrido- [2,3-d]-pyrimidine-6-carbonitrile, a compound of structure (I).
Following the procedure of Example XXII, 5,6,7,8-tetrahydro-8-(2-methoxyethyl)-5-oxo 2 phenylpyrido [2,3- d]-pyrimidine-6-carbonitrile is prepared from 6.5 g. of 4- [(2 cyanoethyl) (2-methoxyethyl)arnino] 2 phenylpyrimidine-S-carboxylic acid, ethyl ester in 50 ml. of ethanol containing 0.46 g. of sodium. During the 2.5 hour reflux period a solid separates. This material is dissolved in 50 ml. water and the aqueous solution is made acidic with 3 N acetic acid solution. The product which deposits out of solution is separated by filtration. Recrystallization from ethanol affords 4.3 g. of product having a melting point of 172-174 C.
Analysis.Calculated for C17H15N4O2 (percent): C, 66.22; H, 5.23; N, 18.17. Found (percent): C, 66.42; H, 5.39; N, 18.08.
EXAMPLES XXXI-XXXII Following the procedure of Example XXII, but substituting an appropriate starting material, the following products are afforded:
(XXXI) 2-(m butoxyphenyl)-8-(2-methoxyethyl)-5,6,7, 8-tetrahydro-5-oxopyrido [2,3-d] pyrimidine-6- I carbonitrile.
(XXXII) S-(butoxyethyl)-2-(o-ethoxyphenyl)-5,6,7,8-
tetrahydro-S-oxopyrido[2,3-d]pyrimidine-6- carbonitrile.
EXAMPLE XXXIII The following illustrates the preparation of 8-(p-chlorobenzyl)-5,6,7,8-tetrahydro 5 oxo-2-'phenylpyrido[2,3- d]-pyrimidine 6 carbonitrile, a compound of structure (1).
Following the procedure of Example XXII, spchlorobenzyl) -5,6,7,8-tetrahydro 5 oxo-2-phenylpyrido [2,3-d]-pyrimidine-6-carhonitrile is prepared from 7.1 g. of 4[p-chlorobenzyl(2-cyanoethyl)amino] 2 phenyl-S- pyrimidinecarboxylic acid, ethyl ester in 50 ml. of ethanol containing 0.39 g. of sodium. Recrystallization of the crude product affords 3.2 g. of pure product, having a melting point of 225-227 C. t
Analysis.Calculated for C H ClN O (percent)? C, 67.29; H, 4.03; Cl, 9.46; N, 14.95. Found (percent): C, 67.11;H,3.98;Cl, 9.75; N, 14.74. 1
EXAMPLES xxxiv-xxxvr Following the procedure of Example XXII but substituting appropriate starting materials, the following products are afforded:
The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed.
9 What is claimed is: 1. A compound selected from the group having the structural formula:
ll j-ON R2 l l Where R is selected from the group consisting of chlorobenzyl, lower alkyl, phenloweralkyl, lower alkoxy (lwer)alkyl and di(lower)alkylamino (lower)a1kyl;
R is selected from the group consisting of lower alkyl, phenyl, halophenyl, lower alkylphenyl, and lower alkoxyphenyl.
2. A compound as defined in claim 1 which is 5,6,7,8-
tetrahydro 8 methyl oXo-2-phenylpyrido[2,3-d]pyrimidine-G-carbonitrile.
3. A compound as defined in claim 1 which is 5,6,7,8- tetr'ahydro 5 oxo-8-phenylethyl-2-pheny1pyrido[2,3-d] pyrimidine-6-carbonitrile.
4. A compound as defined in claim 1 which is 5,6,7,8- tetrahydro 8 (2 methoxyethyl)-5-oXo-2-pheny1pyrido [2,3-d]pyrimidine-6-carbonitrile.
5. A compound as defined in claim 1 which is 8-(pchlorobenzyl) 5,6,7,8 tetrahydro-S-oxo-2-phenylpyrido [2,3-d]pyrimidine-6-carbonitri1e.
References Cited UNITED STATES PATENTS 2,963,480 12/1960 Taylor et al. 260256.4
ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner US. Cl. X.R.
260-247.2 B, 247.5 B, 256.4 N; 424248, 251
US752485A 1968-08-14 1968-08-14 5 6 78-tetrahydro - 5 - oxo-pyrid o(23-d)-pyrimidine - 6 -carbonitriles and related compounds Expired - Lifetime US3641027A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US75248568A 1968-08-14 1968-08-14

Publications (1)

Publication Number Publication Date
US3641027A true US3641027A (en) 1972-02-08

Family

ID=25026504

Family Applications (1)

Application Number Title Priority Date Filing Date
US752485A Expired - Lifetime US3641027A (en) 1968-08-14 1968-08-14 5 6 78-tetrahydro - 5 - oxo-pyrid o(23-d)-pyrimidine - 6 -carbonitriles and related compounds

Country Status (1)

Country Link
US (1) US3641027A (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2194420A1 (en) * 1972-08-02 1974-03-01 Bellon Labor Sa Roger
JPS5058095A (en) * 1973-09-26 1975-05-20
US3886159A (en) * 1974-03-29 1975-05-27 American Home Prod Esters of 6-(substituted)-5,6,7,8-tetra-hydro-8-ethyl-5-oxo-2-(methylthio)pyrido{8 2,3-d{9 pyrimidine-6-carboxylic acids
US4113859A (en) * 1972-10-12 1978-09-12 Burroughs Wellcome Co. Certain pyrido-pyrimidines for treating mammalian and avian infections
DK152498B (en) * 1972-08-02 1988-03-07 Bellon Labor Sa Roger METHOD FOR PREPARING 8-ALKYL-5-OXO-5,8-DIHYDRO-PYRIDO (2,3-D) PYRIMIDINE-6-CARBOXYL ACID

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2194420A1 (en) * 1972-08-02 1974-03-01 Bellon Labor Sa Roger
JPS52106900A (en) * 1972-08-02 1977-09-07 Deito Lab Rogeeru Beron Sa Process for preparing 22ryrodinoo55 oxoo66carboalkoxyy88alkyll5*88 dihydride*2*33d*pyrimidine
JPS52111595A (en) * 1972-08-02 1977-09-19 Deito Lab Rogeeru Beron Sa Process for preparing 55oxoo66 carboalkoxyy88alkyll5*88 dihydride*2*33d*pyrimidines
DK152498B (en) * 1972-08-02 1988-03-07 Bellon Labor Sa Roger METHOD FOR PREPARING 8-ALKYL-5-OXO-5,8-DIHYDRO-PYRIDO (2,3-D) PYRIMIDINE-6-CARBOXYL ACID
US4113859A (en) * 1972-10-12 1978-09-12 Burroughs Wellcome Co. Certain pyrido-pyrimidines for treating mammalian and avian infections
JPS5058095A (en) * 1973-09-26 1975-05-20
US3886159A (en) * 1974-03-29 1975-05-27 American Home Prod Esters of 6-(substituted)-5,6,7,8-tetra-hydro-8-ethyl-5-oxo-2-(methylthio)pyrido{8 2,3-d{9 pyrimidine-6-carboxylic acids

Similar Documents

Publication Publication Date Title
US4923872A (en) Analogues of pyrrolo[3,2d]pyrimidin-4-ones
US4209623A (en) Pyrimidine-5-N-(1H-tetrazol-5-yl)-carboxamides
EP0163599B1 (en) Pyrimidopyrimidine derivatives, processes for producing them, pharmaceutical compositions containing them and their use as anti-allergic agents
US3910913A (en) 4,5-Diamino-7H-pyrrolo{8 2,3-d{9 pyrimidine derivatives
US3950338A (en) 8-alkyl-5-oxo-5,8-dihydro-pyrido(2,3-d)pyrimidine-6-carboxylic acids and their preparation
US5565463A (en) 9-subtituted-8-unsubstituted-9-deazaguanines
EP0260491B1 (en) 9-deazaguanines
US3631036A (en) 5-amino-2 6-substituted-7h-pyrrolo(2 3-d) pyrimidines and related compounds
US4921858A (en) 7-deazaguanines as immunomodulators
US5002950A (en) 7-deazaguanines as immunomodulators
EP0044704B1 (en) Substituted pyrimidin-2-ones, the salts thereof, processes for their preparation, and pharmaceutical compositions containing them
WO2006083553A2 (en) Diketo acids with nucleobase scaffolds: anti-hiv replication inhibitors targeted at hiv integrase
AU8328187A (en) 7-deazaguanines as immunomodulators
KR860000320B1 (en) Method for preparing N-substituted aziridine-2-carboxylic acid derivative
US3732226A (en) 4-((2-cyanoethyl)amino)-2-phenyl-5-pyrimidinecarboxylic acid esters
US3843645A (en) 5,6,7,8-tetrahydro-5-oxo-pyrido(2,3-d)-pyrimidine-6-carbonitriles and related compounds
Lee et al. Antitumor agents. 86. Synthesis and cytotoxicity of. alpha.-methylene-. gamma.-lactone-bearing purines
US5236926A (en) 9-substituted-8-halo or -8-hydroxy-9-deazaguanines as inhibitors or PNP for pharmaceutical compositions
US3850928A (en) Substituted 6-alkylamino-2-phenyl-5-pyrimidine carboxylic acids
US3575977A (en) 7-alkyl-2,5-disubstituted-7h-pyrrolo-(2,3-d)pyrimidines-6-carbonitriles
US3641028A (en) 5-hydroxy - 7h - pyrrolo(2 3-d)pyrimidine-6-carboxylic acid esters and related compounds
US5061707A (en) 9-deazaguanines to treat psoriasis
US3732227A (en) 4-((cyanomethyl)alkylamino)-2-phenyl-5-pyrimidinocarboxylic acids,alkyl esters
US3703517A (en) 4-((carboxyalkyl)amino)-5-pyrimidine-carboxylic acid esters
US3517010A (en) 5-acetamido-4-pyrimidinecarboxylic acids and related compounds